The microRNA miR-33a suppresses IL-6-induced tumor progression by binding Twist in gallbladder cancer

// Mingdi Zhang 1, 2 , Wei Gong 1 , Bin Zuo 3 , Bingfeng Chu 1 , Zhaohui Tang 1 , Yong Zhang 1 , Yong Yang 1 , Di Zhou 1 , Mingzhe Weng 1 , Yiyu Qin 1 , Mingzhe Ma 1 , Alex Jiang 4 , Fei Ma 5 , Zhiwei Quan 1 1 Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China 2 Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China 3 Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China 4 Schulich School of Medicine and Dentistry, Western Ontario University, London, ON N6A 3K6, Canada 5 Department of Oncology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China Correspondence to: Zhiwei Quan, email: zhiwquan@163.com Fei Ma, email: irismafei@126.com Keywords: gallbladder cancer, microRNAs, epithelial–mesenchymal transition, twist, interleukin-6 Received: January 23, 2016      Accepted: September 25, 2016      Published: October 15, 2016 ABSTRACT Cytokine is a key molecular link between chronic inflammation and gallbladder cancer (GBC) progression. The potential mechanism of cytokine-associated modulation of microRNAs (miRNAs) expression in GBC progression is not fully understood. In this study, we investigated the biological effects and prognostic significance of interleukin-6 (IL-6) -induced miRNAs in the development of GBC. We identify that inflammatory cytokine, IL-6 promotes proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of GBC both in vitro and in vivo . Among all the changed miRNAs in miRNA profiling, miR-33a expression was significantly decreased in IL-6 treated GBC cell lines, as well as in GBC tissues compared with case-matched normal tissues and cholecystitis tissues. In turn, miR-33a suppresses IL-6−induced tumor metastasis by directly binding Twist which was identified as an EMT marker. High expression of miR-33a suppressed xenograft tumor growth and dissemination in nude mice. The downregulation of miR-33a was closely associated with advanced clinical stage, lymph node metastasis, and poor clinical outcomes in patients with GBC. miR-33a acts as a tumor suppressor miRNA in GBC progression and may be considered for the development of potential therapeutics against GBC.